Kang Zhen-Hua, Wang Chun-Yan, Zhang Wen-Liang, Zhang Jian-Tao, Yuan Chun-Hua, Zhao Ping-Wei, Lin Yu-Yang, Hong Sen, Li Chen-Yao, Wang Lei
Department of Colorectal and Anus Surgery, First Hospital, Jilin University, Changchun, P. R. China.
The Tumor Research Institute of JiLin Province, Changchun, P. R. China.
PLoS One. 2014 Jun 4;9(6):e98894. doi: 10.1371/journal.pone.0098894. eCollection 2014.
Gastric cancer (GC) is one of the leading causes of cancer death in the world. The role of histone deacetylase 4 (HDAC4) in specific cell and tissue types has been identified. However, its biological roles in the development of gastric cancer remain largely unexplored. Quantitative real time PCR (qRT-PCR) and western blot were used to analyze the expression of HDAC4 in the clinical samples. siRNA and overexpression of HDAC4 and siRNA p21 were used to study functional effects in a proliferation, a colony formation, a adenosine 5'-triphosphate (ATP) assay and reactive oxygen species(ROS) generation, cell cycle, cell apoptosis rates, and autophagy assays. HDAC4 was up-regulated in gastric cancer tissues and several gastric cancer cell lines. The proliferation, colony formation ability and ATP level were enhanced in HDAC4 overexpression SGC-7901 cells, but inhibited in HDAC4 knockdown SGC-7901 cells. HDAC4 knockdown led to G0/G1 phase cell arrest and caused apoptosis and ROS increase. Moreover, HDAC4 was found to inhibit p21 expression in gastric cancer SGC-7901 cells. p21 knockdown dramatically attenuated cell proliferation inhibition, cell cycle arrest, cell apoptosis promotion and autophagy up-regulation in HDAC4-siRNA SGC-7901 cells. We demonstrated that HDAC4 promotes gastric cancer cell progression mediated through the repression of p21. Our results provide an experimental basis for understanding the pro-tumor mechanism of HDAC4 as treatment for gastric cancer.
胃癌（GC）是全球癌症死亡的主要原因之一。组蛋白去乙酰化酶4（HDAC4）在特定细胞和组织类型中的作用已得到确认。然而，其在胃癌发生发展中的生物学作用仍 largely 未被探索。采用定量实时PCR（qRT-PCR）和蛋白质免疫印迹法分析临床样本中HDAC4的表达。利用HDAC4的 siRNA和过表达以及 siRNA p21来研究其在细胞增殖、集落形成、三磷酸腺苷（ATP）检测、活性氧（ROS）生成、细胞周期、细胞凋亡率和自噬检测中的功能效应。HDAC4在胃癌组织和几种胃癌细胞系中上调。HDAC4过表达的SGC-7901细胞的增殖、集落形成能力和ATP水平增强，但HDAC4敲低的SGC-7901细胞中则受到抑制。HDAC4敲低导致细胞停滞于G0/G1期，并引起细胞凋亡和ROS增加。此外，发现HDAC4在胃癌SGC-7901细胞中抑制p21表达。p21敲低显著减弱了HDAC4-siRNA SGC-7901细胞中的细胞增殖抑制、细胞周期停滞、细胞凋亡促进和自噬上调。我们证明HDAC4通过抑制p21介导促进胃癌细胞进展。我们的结果为理解HDAC4的促肿瘤机制作为胃癌治疗提供了实验依据。
